The mannose receptor represents a paradigm for the involvement of C-type lectins in clearance of circulating glycoproteins. The role of glycan-binding receptors as tags for uptake and turnover was one of the first established functions for endogenous sugar-binding proteins and provides a key model for how glycans can modulate communication between cells in a physiological context. While the asialoglycoprotein receptor would be considered the founder member of this group of receptors, the in vivo evidence for its function is less compelling than the results for the mannose receptor, which has well defined roles in clearance of sulfated glycoprotein hormones as well as mannose-bearing glycoproteins released at sites of inflammation.
In addition to the mannose receptor and the asialoglycoprotein receptor, the scavenger receptor C-type lectin may also be involved in clearance of serum glycoproteins. The asialoglycoprotein receptor and the scavenger receptor C-type lectin have different domain organisations and ligand binding specificities compared to the mannose receptor.
CFG Participating Investigators contributing to the understanding of this paradigm
PIs working with the mannose receptor include: Ten Feizi; Reiko Lee; Yuan Lee; Michel Nussenzweig; Maureen Taylor; Kurt Drickamer; Chi-Huey Wong; Bill Weis; Pauline Rudd; Nathalie Scholler
Progress toward understanding this GBP paradigm
This section documents what is currently known about the mannose receptor, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Pages for the human and mouse mannose receptor in the CFG database.
As in the case of the selectins, much of the evidence for functions of the mannose receptor pre-dates the consortium. However, there have been some further developments for this receptor and other members of the group. PIs have generated and characterized knockout mice, defined the sugar-binding specificities, demonstrated clearance in vivo and endocytosis in tissue culture, and performed structural analysis.
The multiple domains in the extracellular region of the mannose receptor allow recognition of a diverse range of glycoconjugate ligands. Several of the eight C-type carbohydrate-recognition domains are involved in Ca2+-dependent recognition of terminal mannose, GlcNAc or fucose residues on the oligosaccharides of endogenous glycoproteins or the surfaces of microorganisms, while the R-type carbohydrate-recognition domain binds sulfated GalNAc and sulfated galactose residues. Biological ligands for the mannose receptor include lysosomal hydrolases, the pro-collagen peptides of type I and type III collagens and tissue plasminogen activator – proteins that bear high mannose oligosaccharides and are released from cells at sites of inflammation. The main biological ligands recognized by the R-type carbohydrate-recognition domain are the pituitary hormones lutropin and thyrotropin which bear oligosaccharides terminating in GalNAc-4-SO4.The CFG contributed to defining specificity for oligosaccharides through screening of glycan arrays.
Cellular expression of GBP and ligands
The mannose receptor was first identified in the liver on sinusoidal endothelial cells and Kupffer cells. The receptor has since been found on most types of tissue macrophages, including those in the placenta and the brain, but not on circulating monocytes. The mannose receptor is also expressed in the retinal pigmented epithelium and on CD1-positive dendritic cells. The CFG contributed to defining expression of the mannose receptor by glycogene microarray analysis
Biosynthesis of ligands
Glycans on endogenous glycoprotein ligands
Two transferases expressed in the pituitary are required to synthesize the terminal GalNAc-4-SO4 residues found on the oligosaccharides of hormones such as lutropin. The protein-specific glycoprotein hormone N-acetylgalactosaminyltransferase (protein-specific β1,4GalNAcT) adds GalNAc which is then sulfated by a GalNAc-4-sulfotransferase (GalNAc-4-ST1).
High mannose oligosaccharides on released lysosomal enzymes are generated from mannose 6-phosphate-containing oligosaccharides (M6PR) by phosphatase activity.
Glycans on micro-organisms
Biosynthesis mannans on fungi has been well studied in a number of species. For example, in the yeast S. cerevisiae, the KRE2/MNT1 genes encode mannosyltransferases that synthesize both N- and O-linked mannans.
The mycobacterial transferases for synthesis of the lipo-arabinomannan (LAM) core and the extended ManLAM structures have been characterized.
The mannose receptor is a type I transmembrane protein, with a large extracellular domain containing three types of domain. An N-terminal R-type carbohydrate-recognition domain is followed by a fibronectin type II domain and eight C-type carbohydrate-recognition domains. The short cytoplasmic C-terminal domain contains a di-aromatic motif essential for rapid internalization and endosomal sorting. The structures of two portions of the extracellular domain of the mannose receptor have been determined. The structure of CRD-4 that has been determined represents the conformation when the receptor relases ligand under endosomal conditions (CRD-4). The structure of the R-type CRD has been determined with bound SO4-GalNAc as well as with other sulfated ligands (R-type CRD with SO4-GalNAc).
Three other endocytic receptors, DEC-205, Endo-180 and the phospholipase A2 receptor, share the same domain organization as the mannose receptor. Of these, only Endo-180 has been shown to bind carbohydrate ligands.
Biological roles of GBP-ligand interaction
The mannose receptor mediates endocytosis of glycoproteins. Ligand-receptor complexes are internalized via clathrin-coated pits into early endosomes where the ligands are released and targeted to the lysosome for degradation. The mannose receptor acts to regulate serum levels of proteins such as lysosomal enzymes that are released from cells during inflammation. The mannose receptor also regulates levels of pituitary hormones such as lutropin and thyrotropin that must be removed from serum once they have acted on their target cells. The mannose receptor can also bind and mediate internalization of a wide variety of pathogenic micro-organisms including HIV, the fungi Candida albicans and Aspergillus fumigatus, parasites such as Leishmania donovani and bacteria including Pneumocystis carinii. The receptor may contribute to the innate immune response to these pathogens. In contrast, the mannose receptor appears to enhance infection of macrophages with mycobacteria, including Mycobacterium tuberculosis. The mannose receptor facilitates entry of mycobacteria into macrophages, where they survive and multiply due to inhibition of phagosome-lysosome fusion.
CFG resources used in investigations
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for "mannose receptor".
The mannose receptor binds carbohydrate structures on serum glycoproteins or the surfaces of pathogens so glycan profiling of mammalian cells is not expected to contribute to the understanding of the biology of this receptor.
Probes for the mannose receptor are included on the CFG glycogene chip. The CFG analyzed patterns of mannose receptor expression showing expression in a wide range of tissues of immune as well as non-immune origin, consistent with localization in tissue macrophages.
Knockout mouse lines
Mice lacking the mannose receptor have been described. Before funding for knockout mice was discontinued, the CFG developed the DNA construct to create a mouse line lacking the scavenger receptor C-type lectin. The construct can now be obtained from the Mutant Mouse Regional Resource Center (MMRRC) at the University of California, Davis.
The CFG analyzed the oligosaccharide-binding specificities of the mannose receptor (example), showing specificity for high mannose oligosaccharides and structures with terminal 6, 3, or 4-sulfated galactose. See all glycan array results for the mannose receptor here.
The CFG has also analyzed the oligosaccharide binding-specificities of the other C-type lectins involved in glycoprotein clearance. The scavenger receptor C-type lectin was shown to be highly specific for oligosaccharides containing the Lewisx trisaccharide or related structures. See glycan array data for the human scavenger receptor here. See the mouse scavenger receptor data here. Glycan array screening with the major subunit of the asialoglycoprotein receptor showed binding to a broad range of galactose- and GalNAc- terminated oligosaccharides, but indicated stronger binding to structures with terminal GalNAc residues.
- ↑ 1.0 1.1 1.2 Taylor PR, Gordon S, Martinez-Pomares L (2005) The mannose receptor: linking homeostasis and immunity through sugar recognition. Trends Immunol 26,104-110
- ↑ 2.0 2.1 Taylor, ME, Conary, JT, Lennartz, MR, Stahl, PD, Drickamer, K (1990) Primary structure of the mannose receptor contains multiple motifs resembling carbohydrate-recognition domains.J Biol Chem 265,12156-12162
- ↑ Taylor, ME., Bezouska, K, Drickamer, K (1992) Contribution to ligand binding by multiple carbohydrate-recognition domains in the macrophage mannose receptor. J Biol Chem 267, 1710-1726
- ↑ Mullin, NP, Hitchen, PG, Taylor, ME (1997) Mechanism of 2+- and monosaccharide-binding to a C-type carbohydrate-recognition domain of the macrophage mannose receptor. J Biol Chem 272, 5668-5681
- ↑ 5.0 5.1 Fiete DJ, Beranek MC, Baenziger JU (1998) A cysteine-rich domain of the "mannose" receptor mediates GalNAc-4-SO4 binding. Proc Natl Acad Sci USA 95, 2089-2093
- ↑ 6.0 6.1 Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC (2002) Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 295, 1898-1901
- ↑ Liu Y, Chirino AJ, Misulovin Z, Leteux C, Feizi T, Nussenzweig MC, Bjorkman PJ. (2000) Crystal structure of the cysteine-rich domain of the mannose receptor complexed with a sulfated carbohydrate ligand. J Exp Med 191, 1105-1116
- ↑ 8.0 8.1 Hsu TL, Cheng SC, Yang WB, Chin SW, Chen BH, Huang MT, Hsieh SL, Wong CH (2009) Profiling carbohydrate-receptor interaction with recombinant innate immunity receptor-Fc fusion proteins. J Biol Chem 284, 34479-34489
- ↑ Schlesinger P, Doebber TW, Mandell BF, White R, DeSchryver C, Rodman JS, Miller MJ, Stahl P (1978) Plasma clearance of glycoproteins with terminal mannose and GlcNAc by liver non-parenchymal cells. Biochem J 176, 103-109
- ↑ Greaton CJ, Lane KB, Shepherd VL, McLaughlin BJ (2003) Transcription of a single mannose receptor gene by macrophage and retinal pigment epithelium. Opthalmic Res 35, 42-47
- ↑ Sallusto F, Cella M, Danieli C, Lanzavecchia A (1995) Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major hitocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J Exp Med 182, 389-400
- ↑ 12.0 12.1 Comelli, EM, Head, SR, Gilmartin, T, Whisenant, T, Haslam, SM, North SJ, Wong, N-K, Kudo, T, Narimatsu, H, Esko, JD, Drickamer, K, Dell, A, Paulson, JC (2006) A focused microarray approach to functional glycomics: transcriptional regulation of the glycome. Glycobiology 16, 117-131
- ↑ Mengeling BJ, Manzella SM, and Baenziger JU (1999) A cluster of basic amino acids within an α-helix is essential for α-subunit recognition by the glycoprotein hormone N-acetylgalactosaminyltransferase. Proc. Natl. Acad. Sci. U.S.A. 92, 502–506
- ↑ Boregowda RK, Mi Y, Bu H, and Baenziger JU (2005) Differential expression and enzymatic properties of GalNAc-4-sulfotransferase-1 and GalNAc-4-sulfotransferase-2. Glycobiology 15, 1349–1358
- ↑ Lussier, M, Sdicu, A-M and Bussey, H (1999) The KTR and MNN1 mannosyltransferase families of Saccharomyces cerevisiae. Biochim. Biophys. Acta 1426, 323-334
- ↑ Tam, P-H and Lowary, TL (2009) Recent advances in mycobacterial cell wall glycan biosynthesis. Cur. Opin Struct. Biol. 13, 618-625
- ↑ 17.0 17.1 Schweizer A, Stahl PD, Rohrer J (2000) A di-aromatic motif in the cytosolic tail of the mannose receptor mediates endosomal sorting. J Biol Chem 275, 29694-29700
- ↑ Taylor, ME (1997) Evolution of a family of receptors containing multiple C-type carbohydrate-recognition domains. Glycobiology 7, v-viii
- ↑ Mi Y, Shapiro SD, Baenziger JU (2002) Regulation of lutropin circulatory half-life by the mannose/N-acetylgalactosamine-4-SO4 receptor is critical for implantation in vivo. J Clin Invest 109, 269-276
- ↑ Kang PB, Azad AK, Torrelles JB, Kaufman TM, Beharka A, Tibesar E, DesJardin LE, Schlesinger LS (2005) The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis. J Exp Med 202, 987-999
- ↑ Swain, SD, Lee, SJ, Nussenzweig, MC, and Harmsen, AG (2003) Absence of the macrophage mannose receptor in mice does not increase susceptibility to Pneumocystis carinii infection in vivo. Infect. Immun. 71, 6213-6221
- ↑ Coombs, PJ, Graham, SA, Drickamer, K, Taylor, ME (2005) Selective binding of the scavenger receptor C-type lectin to LewisX trisaccharide and related glycan ligands. J Biol Chem 280, 22993-22999
- ↑ Feinberg H, Taylor ME, Weis WI (2007) Scavenger receptor C-type lectin binds to the leukocyte cell surface glycan Lewis(x) by a novel mechanism. J Biol Chem 282, 17250-17258
- ↑ Coombs, PJ, Taylor, ME, Drickamer, K (2006) Two categories of mammalian galactose-binding receptors distinguished by glycan array profiling. Glycobiology 16, 1C-7C
The CFG is grateful to the following PIs for their contributions to this wiki page: Maureen Taylor, Kurt Drickamer